Many environmental and intrinsic factors influence cognitive function. Intrinsic factors that can influence cognitive function include sex, age and genetic makeup.
Sex Differences in Cognitive Function
Effects of sex on cognitive function have been shown in humans and animal models using established tests. Sex differences have been demonstrated in both episodic memory tasks (favoring women) and spatial visualization tasks (favoring men). Interestingly, in some studies alcohol consumption abolished sex differences in spatial visualization, but not episodic memory performance. In addition, stress has been shown to differentially affect fear conditioning in men and women.
Consistent with the human studies, effects of sex on cognitive function have also been reported in animal models using established tests. In general, studies of spatial learning and memory in rodents have shown that males learn more quickly than females and exhibit superior performance in a variety of mazes. Some studies, however, have not shown such differences between the sexes. Sex differences in classical fear conditioning and shuttlebox avoidance conditioning in rats have also been reported. In addition, in some studies neonatal isolation facilitated appetitive response learning in adult female, but not male, rats.
Cognitive tests administered to humans and animals frequently involve large differences. Therefore, it often remains difficult to directly compare results on these tests across species. For example, while spatial learning and memory can be easily assessed in humans and animal models, to compare assessments of spatial learning and memory in humans and mice, navigation to a target can be important. In some tests of spatial memory, when all the information is within one field of view, the participant has an aerial perspective and a body-centered (egocentric) frame of reference (e.g. table-top tests of spatial memory). Such tests are routinely used to assess visuospatial memory, but are very different from tests of spatial memory typically used for rodents. Testing visuospatial memory in rodents typically involves a viewer perspective of a world-centered (allocentric) frame of reference with information found throughout a complex environment in which the participant has to navigate. Making direct inferences about performance on navigation tests from performance on table-top tests can be problematic.
Virtual reality (“VR”), which has been used to assess, expose, and desensitize (in phobias) event and place-related memories, to assess and teach driving and flying skills, and to distract in pain management, can also be used to assess spatial learning and memory in humans using a navigational task. Navigation in a virtual environment has been shown to be sensitive to effects of sex of participants in some, but not all, studies. In one study, a virtual environment consisting of a series of interconnected hallways, some leading to dead ends and others leading to a designated goal location, was used to study age and sex differences in spatial navigation. In this study, there was no significant effect of sex on time to complete the maze or total distance traveled, but there was an effect of sex on total number of deviations from the correct route into a dead-end corridor, and there was an effect of sex on how often participants traveled on a portion of the correct route through which they had already traveled. However, as there was no cued version of this test, it is difficult to distinguish task learning performance from spatial learning and memory performance. In another study from the same authors, a virtual water maze environment was used to study the effects of age and sex on spatial learning and memory in humans. (The water maze paradigm is commonly used to assess spatial learning and memory in rodents.) An effect of age, but not of sex, was detected on performance. In this study, a trial with a visible target was given following the trials with a hidden target.
Apolipoprotein E (APOE) Genotype and Age Differences in Cognitive Function
The three major human isoforms of apolipoprotein E (APOE), which are encoded by distinct APOE alleles (ε2, ε3, and ε4), are involved in the metabolism and redistribution of lipoproteins and cholesterol. Compared with ε2 and ε3, ε4 is associated with increased risk of cognitive impairments and of developing Alzheimer's disease (AD). Women are at higher risk to develop AD than men, particularly women carrying ε4. In contrast to the risk to develop AD, the effects of ε4 on cognitive function in the non-demented elderly old-old (>75 years of age) are less clear. While some studies have shown poor cognitive performance in non-demented elderly ε4 carriers compared with non-demented elderly non-ε4 carriers and a small effect was observed in a meta-analysis, other studies did not.
In the elderly, high cortisol and low testosterone levels might contribute to reduced cognitive function. In older men and women, higher cortisol levels have been associated with poorer cognitive performance in some studies. However, in another study cortisol levels only inversely correlated with paragraph recall in older participants with mild cognitive impairment (MCI) but not in elderly control participants. APOE genotype might also influence cortisol levels. In AD patients, higher cerebrospinal cortisol levels in ε4 than non-ε4 carriers have been reported, although comparable cerebrospinal cortisol in non-ε4 and ε4 carriers have also been reported. In elderly men, low testosterone levels might also contribute to reduced cognitive function. In older men, testosterone levels have been positively correlated with cognitive function, and cognitive function could be improved by testosterone treatments. Similarly, testosterone, but not estrogen, levels in serum have correlated positively with cognitive performance in older women, and androgen therapy has been shown to improve cognition in surgically menopausal women. The relationship between testosterone levels and cognitive function might be ε4-dependent. In men, low testosterone levels and ε4 have been shown to interact in increasing the risk of developing AD. In addition, an interaction between ε4 and cognitive performance in healthy older men has been reported; while in non-ε4 carriers higher testosterone levels were associated with better general cognition, in ε4 carriers higher testosterone levels were associated with lower cognitive performance.